The formation of the intricate neuronal network in the brain requires precise neurogenesis and neuronalmigration followed by neurite and spine formation during development. If neurite and spine formation isdisrupted, it results in a wide range of diseases such as mental illnesses. Recently, patients with amicroduplication of the 17p13.3 chromosome region have been reported and the number of patients exhibitingthis syndrome has been increasing. Interestingly, the patients with this 17p13.3 microduplication syndromeshow severe neurological and morphological defects, including, epilepsy, mental retardation and autismspectrum disorders (ASD). More interestingly, the studies analyzing this new human genetic syndrome clarifiedthat the critical region spanning about 70kb is strongly associated with ASD, and this region contains a singlegene, Ywhae, encoding the protein 14-3-3ε. These data strongly suggest that Ywhae might be responsible forthe ASD phenotype in these patients. The functions of 14-3-3ε in neuronal morphogenesis including neuriteformation, have not been previously analyzed and still remain unknown. Therefore, the objectives of thisresearch proposal are to analyze the novel in vivo functions and molecular targets of 14-3-3ε in neuriteformation, in particular neurite initiation and extension, and clarifying the molecular mechanisms in this cellularevent. We hypothesize that 14-3-3ε plays an important role in neurite initiation as well as neurite extension bycontrolling microtubule (MT) sliding and stability through binding to Doublecortin (Dcx) and Microtubule affinityregulating kinase 3 (Mark3). To test this hypothesis, we propose to use a wide variety of experimental strategiesincluding in utero electroporation, time-lapse live imaging in vitro and in vivo, tamoxifen-inducible Cre-loxPsystem, and 14-3-3ε conditional knockout mice. We have three specific aims. In the Specific Aim 1, we will testthe hypothesis that 14-3-3ε regulates neurite formation and synaptogenesis. In Specific Aim 2, the hypothesisthat 14-3-3ε regulates neurite initiation in the cortex by regulating MT sliding through binding to Dcx will betested. In Specific Aim 3, we will test the hypothesis that 14-3-3ε regulates neurite extension by binding toMark3 and regulating its activity. The successful completion of this project will not only provide understanding asto the etiology of a new human genetic syndrome strongly associating with ASD caused by the overexpressionof 14-3-3ε but also significantly enhance our understanding of the precise in vivo functions of 14-3-3ε in neuriteinitiation and extension.
Interagency Autism Coordinating Committee (IACC)
Autism Research Database (AFD)
